scholarly journals The Role of the Cullin-5 E3 Ubiquitin Ligase in the Regulation of Insulin Receptor Substrate-1

2012 ◽  
Vol 2012 ◽  
pp. 1-8
Author(s):  
Christine Zhiwen Hu ◽  
Jaswinder K. Sethi ◽  
Thilo Hagen
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Ubiquitin Ligases ◽  
Insulin Receptor Substrate ◽  
E3 Ubiquitin Ligases ◽  
Kinase C ◽  
Cullin 5 ◽  
Socs Proteins ◽  
Protein Kinase C Activation

Background. SOCS proteins are known to negatively regulate insulin signaling by inhibiting insulin receptor substrate-1 (IRS1). IRS1 has been reported to be a substrate for ubiquitin-dependent proteasomal degradation. Given that SOCS proteins can function as substrate receptor subunits of Cullin-5 E3 ubiquitin ligases, we examined whether Cullin-5 dependent ubiquitination is involved in the regulation of basal IRS1 protein stability and signal-induced IRS1 degradation.Findings. Our results indicate that basal IRS1 stability varies between cell types. However, the Cullin-5 E3 ligase does not play a major role in mediating IRS1 ubiquitination under basal conditions. Protein kinase C activation triggered pronounced IRS1 destabilization. However, this effect was also independent of the function of Cullin-5 E3 ubiquitin ligases.Conclusions. In conclusion, SOCS proteins do not exert a negative regulatory effect on IRS1 by functioning as substrate receptors for Cullin-5-based E3 ubiquitin ligases both under basal conditions and when IRS1 degradation is induced by protein kinase C activation.

scholarly journals Shp2 Is Required for Protein Kinase C-dependent Phosphorylation of Serine 307 in Insulin Receptor Substrate-1

2005 ◽  
Vol 280 (38) ◽  
pp. 32693-32699 ◽  
Author(s):  
Karsten Müssig ◽  
Harald Staiger ◽  
Hendrik Fiedler ◽  
Klaus Moeschel ◽  
Alexander Beck ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Kinase C

scholarly journals Phosphorylation of Ser357of Rat Insulin Receptor Substrate-1 Mediates Adverse Effects of Protein Kinase C-δ on Insulin Action in Skeletal Muscle Cells

2008 ◽  
Vol 283 (17) ◽  
pp. 11226-11233 ◽  
Author(s):  
Rizwana Sanaullah Waraich ◽  
Cora Weigert ◽  
Hubert Kalbacher ◽  
Anita M. Hennige ◽  
Stefan Z. Lutz ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Adverse Effects ◽  
Insulin Receptor ◽  
Insulin Action ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Insulin Receptor Substrate ◽  
Kinase C

scholarly journals Protein Kinase C-ζ Phosphorylates Insulin Receptor Substrate-1, -3, and -4 But Not -2: Isoform Specific Determinants of Specificity in Insulin Signaling

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2451-2458 ◽  
Author(s):  
Sihoon Lee ◽  
Edward G. Lynn ◽  
Jeong-a Kim ◽  
Michael J. Quon
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Negative Feedback ◽  
Insulin Signaling ◽  
Kinase Assay ◽  
Insulin Receptor Substrate ◽  
Kinase C ◽  
Pi3k Activity ◽  
Pkc Ζ

Protein kinase C-ζ, a downstream effector of phosphatidylinositol 3-kinase (PI3K), phosphorylates insulin receptor substrate (IRS)-1 on serine residues impairing activation of PI3K in response to insulin. Because IRS-1 is upstream from PI3K, this represents a negative feedback mechanism that may contribute to signal specificity in insulin action. To determine whether similar feedback pathways exist for other IRS isoforms, we evaluated IRS-2, -3, and -4 as substrates for PKC-ζ. In an in vitro kinase assay, purified recombinant PKC-ζ phosphorylated IRS-1, -3 and -4 but not IRS-2. Similar results were obtained with an immune-complex kinase assay demonstrating that wild-type, but not kinase-deficient mutant PKC-ζ, phosphorylated IRS-1, -3, and -4 but not IRS-2. We evaluated functional consequences of serine phosphorylation of IRS isoforms by PKC-ζ in NIH-3T3IR cells cotransfected with epitope-tagged IRS proteins and either PKC-ζ or empty vector control. Insulin-stimulated IRS tyrosine phosphorylation was impaired by overepxression of PKC-ζ for IRS-1, -3, and -4 but not IRS-2. Significant insulin-stimulated increases in PI3K activity was coimmunoprecipitated with all IRS isoforms. In cells overexpressing PKC-ζ there was marked inhibition of insulin-stimulated PI3K activity associated with IRS-1, -3 and -4 but not IRS-2. That is, PI3K activity associated with IRS-2 in response to insulin was similar in control cells and cells overexpressing PKC-ζ. We conclude that IRS-3 and -4 are novel substrates for PKC-ζ that may participate in a negative feedback pathway for insulin signaling similar to IRS-1. The inability of PKC-ζ to phosphorylate IRS-2 may help determine specific functional roles for IRS-2.

scholarly journals Protein kinase C activators selectively inhibit insulin-stimulated system A transport activity in skeletal muscle at a post-receptor level

1990 ◽  
Vol 268 (3) ◽  
pp. 633-639 ◽  
Author(s):  
A Gumà ◽  
M Camps ◽  
M Palacín ◽  
X Testar ◽  
A Zorzano
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Insulin Action ◽  
Phorbol Esters ◽  
Polymyxin B ◽  
Transport Activity ◽  
System A ◽  
Kinase C ◽  
Protein Kinase C Activation

We have investigated the role of phorbol esters on different biological effects induced by insulin in muscle, such as activation of system A transport activity, glucose utilization and insulin receptor function. System A transport activity was measured by monitoring the uptake of the system A-specific analogue alpha-(methyl)aminoisobutyric acid (MeAIB), by intact rat extensor digitorum longus muscle. The addition of 12-O-tetradecanoylphorbol 13-acetate (TPA, 0.5 microM) for 60 or 180 min did not modify basal MeAIB uptake by muscle, suggesting that insulin signalling required to stimulate MeAIB transport does not involve protein kinase C activation. However, TPA added 30 min before insulin (100 nM) markedly inhibited insulin-stimulated MeAIB uptake. The addition of polymyxin B (0.1 mM) or H-7 (1 mM), protein kinase C inhibitors, alone or in combination with TPA leads to impairment of insulin-stimulated MeAIB uptake. This paradoxical pattern is incompatible with a unique action of Polymyxin B or H-7 on protein kinase C activity. Therefore these agents are not suitable tools with which to investigate whether a certain insulin effect is mediated by protein kinase C. TPA did not cause a generalized inhibition of insulin action. Thus both TPA and insulin increased 3-O-methylglucose uptake by muscle, and their effects were not additive. Furthermore, TPA did not modify insulin-stimulated lactate production by muscle. In keeping with this selective modification of insulin action, treatment of muscles with TPA did not modify insulin receptor binding or kinase activities. In conclusion, phorbol esters do not mimic insulin action on system A transport activity; however, they markedly inhibit insulin-stimulated amino acid transport, with no modification of insulin receptor function in rat skeletal muscle. It is suggested that protein kinase C activation causes a selective post-receptor modification on the biochemical pathway by which insulin activates system A amino acid transport in muscle.

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